Untersuchung des spannungsabhängigen Chloridkanals CIC-2 in Neuronen - Ursache für Epilepsie?
Zusammenfassung der Projektergebnisse
In contrast to the well characterized GABAA receptors, the function of voltage-gated chloride channels in neurons was primarily elusive. The voltage gated chloride channels ClC-2 has been suggested to be involved in regulating chloride homeostasis, and excitability. ClC-2 is an almost ubiquitously expressed chloride channel of the CLC family of chloride channels and transporters. ClC-2 is activated by negative membrane voltage, cell swelling, a rise in intracellular chloride concentration, or mild extracellular acidification. The loss of ClC-2 in mice has profound effects leading to testicular and retinal degeneration. Recently, in aged knockout (KO) animals, a spongiform vacuolation of the white matter in the CNS was reported, which might be related to defective oligodendrocyte function. Although currents with properties similar to ClC-2 have been described in neurons, the molecular identity and the function of this current remained unclear. This work revealed an important role of ClC-2 in neuronal excitability. ClC-2 is not only expressed in pyramidal neurons but also in a subset of inhibitory interneurons. The loss of ClC- 2 in interneurons increases inhibition mediated by a higher excitability of a subpopulation of interneurons. The increased inhibition might balance hyperexcitability of the network, thereby preventing epilepsy in ClC-2 knock-out mice. Together, we suggest that ClC-2 in neurons regulates excitability via the membrane resistance and provides an additional efflux pathway for chloride. The effects on membrane resistance pose the question whether ClC-2 is regulated by neuronal activity, for example, by changing extracellular pH or PKC activity, thereby regulating neuronal excitability.
Projektbezogene Publikationen (Auswahl)
- (2010) ClC-2 Voltage-Gated Channels Constitute Part of the Background Conductance and Assist Chloride Extrusion. Journal of Neuroscience 30:4776-4786
Rinke I, Artmann J, Stein V
